New treatments for NASH Vincent Wong Institute of Digestive Disease - - PowerPoint PPT Presentation

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New treatments for NASH Vincent Wong Institute of Digestive Disease - - PowerPoint PPT Presentation

Nov 15, 2023 2.89k likes •3.24k views

New treatments for NASH Vincent Wong Institute of Digestive Disease The Chinese University of Hong Kong Disclosures Consultancy: AbbVie, Allergan, Gilead Sciences, Janssen, Perspectum Diagnostics, Pfizer Lectures: Bristol-Myers

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Vincent Wong Institute of Digestive Disease The Chinese University of Hong Kong

New treatments for NASH

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Disclosures

  • Consultancy: AbbVie, Allergan, Gilead Sciences,

Janssen, Perspectum Diagnostics, Pfizer

  • Lectures: Bristol-Myers Squibb, Echosens, Gilead

Sciences, Merck

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25% of the global population has non-alcoholic fatty liver disease (NAFLD)

13% 27% 24% 32% 24% 30% Modified from Younossi et al. Hepatology 2016;64:73

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Natural history of NAFLD in Asia

Fan JG, Kim SU, Wong VW. J Hepatol 2017;67:862

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Management of NAFLD

Disease stage NAFL NASH NASH-related cirrhosis Lifestyle modification

✓ ✓ ✓

Statin if indicated

✓ ✓ ✓

Pharmacological treatment

✓ ✓

Screening for varices and HCC HCC?

✓

Bariatric surgery For morbid

  • besity

For morbid

  • besity

For morbid

  • besity
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SLIDE 6

Dulai et al. Hepatology 2017;65:1557

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Lifestyle modification and resolution of NAFLD/NASH

Wong VW et al. J Hepatol 2013;59:536 Vilar-Gomez et al. Gastroenterology 2015;49:367

%

≥10% weight loss achieved in:

  • 19% of patients

in a community cohort (Wong et al.)

  • 10% of patients

in a hospital cohort (Vilar- Gomez et al.)

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Pharmacological treatment of NASH

Vitamin E

  • Anti-oxidant
  • Reduces liver fat and

inflammation

  • Neutral effects on insulin

resistance

  • Uncertain effects on the

cardiovascular system and malignancy

Pioglitazone

  • Insulin sensitizer
  • Reduces liver fat and

inflammation

  • Causes weight gain ±

fluid retention

  • May increase the risk of

bladder cancer

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Liraglutide (GLP-1 agonist)

GLP-1: glucagon-like peptide 1 LEADER Trial

Primary outcome: death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke

Marso et al. NEJM 2016;375:311

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Liraglutide for NASH (LEAN Study)

Outcomes Liraglutide Placebo P N 23 22 Resolution of NASH 39% 9% 0.019 Improved ballooning 61% 32% 0.05 Improved steatosis 83% 45% 0.009 Improved lobular inflammation 48% 55% 0.65 Improved fibrosis 26% 14% 0.46 Worsened fibrosis 9% 36% 0.04

Armstrong et al. Lancet 2016;387:679

Down side:

  • Requires injections
  • GI upset
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Bile acids and NAFLD

Arab et al. Hepatology 2017;65:350 FXR Farnesoid X receptor

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Obeticholic acid in NASH – FLINT study

45 22 35 61 53 12 46 21 13 19 38 35 13 31

10 20 30 40 50 60 70 Primary

  • utcome

Resolution of NASH Fibrosis improvement Steatosis improvement Lobular inflammation improvement Portal inflammation improvement Ballooning improvement OCA (n=110) Placebo (n=109) %

Primary outcome = NAS decrease ≥2 points without worsening of fibrosis at 72 weeks Neuschwander-Tetri et al. Lancet 2015;385:956

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Safety of obeticholic acid

OCA Placebo Pruritus 23% 6% Change in lipids (mmol/L) Total cholesterol 0.16

  • 0.19

HDL-C

  • 0.02

0.03 LDL-C 0.22

  • 0.22

Triglycerides

  • 0.22
  • 0.08

2 deaths in the OCA arm

  • Congestive heart failure and sepsis
  • Myocardial ischemia

Neuschwander-Tetri et al. Lancet 2015;385:956

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Relationship between cholesterol and bile acid synthesis

https://commons.wikimedia.org/wiki/File:Bile_acid_differentiation.svg

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GS-9674, a non-steroidal, intestine- selective FXR agonist

T r i a c y lg ly c e r id e ( µ m o l/g ) 2 0 4 0 6 0 8 0

* * *

Hepatic Triglycerides

Vehicle BID GS-9674 10 mg/kg QD GS-9674 30 mg/kg QD GS-9674 30 mg/kg BID

5 10 15 20 300 600 900 1200

*

Serum LDL-C

mg/dL

5 1 0 1 5 2 0 5 0 1 0 0 1 5 0 2 0 0

Serum HDL-C

5 10 15 20 500 1000 1500

*

Serum Cholesterol

GS-9674 30 mg/kg BID Vehicle Treatment start HDL-C, high-density lipoprotein-cholesterol; LDL-C; low-density lipoprotein-cholesterol. French D, et al., AASLD 2016 (oral presentation) High-fat diet cynomolgus monkey model

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Peroxisome proliferator-activated receptors (PPARs)

Blaschke et al. Arterioscler Thromb Vasc Biol 2006;26:28

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Elafibranor: a dual PPARα/δ agonist

  • Improves insulin sensitivity and lipids
  • Well tolerated apart from abdominal pain (~10%) and small increase

in serum creatinine

Outcomes of the GOLDEN-505 Study N Placebo Elafibranor 80 mg Elafibranor 120 mg P Protocol-defined primary outcome: Absence of steatosis, lobular inflammation or ballooning without worsening of fibrosis Total 274 17% 23% 21% 0.28 NAS ≥4 234 11% 20% 20% 0.018 Modified definition: Resolution of NASH – Ballooning = 0 and lobular inflammation = 0-1 Total 274 12% 13% 19% 0.045 NAS ≥4 234 9% 13% 19% 0.013

Ratziu et al. Gastroenterology 2016;150:1147

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Rationale of ASK1 inhibition for NASH

  • ASK1 pathway activated

in NASH and correlates with fibrosis stage

  • In rodent models, ASK1

inhibition improves steatosis, inflammation and fibrosis

  • GS-4997 (selonsertib) is

a selective, potent (EC50 10.8 nM), small molecule inhibitor of ASK1

ASK1, apoptosis signal-regulating kinase 1 Loomba et al. AASLD Late-breaking Abstract #3

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Fibrosis improvement with selonsertib treatment for 6 months

Loomba et al. Hepatology 2017 [Epub ahead of print]

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Cenicriviroc: a dual CCR2/5 antagonist

  • Blocks Kupffer cell

activation and macrophage recruitment

  • Anti-inflammatory and anti-

fibrotic activity in animal models

  • Favorable safety profile

8 20 6 10 5 10 15 20 25 NASH resolution without worsening of fibrosis Fibrosis improvement without worsening of NASH CVC (n=145) Placebo (n=144) % Friedman et al. Hepatology 2017 [Epub ahead of print] Phase 2b CENTAUR study Primary analysis at Year 1

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BMS-986036 (Pegylated FGF21)

Improved liver fat by MRI-PDFF Improved liver stiffness by MRE Sanyal et al. AASLD 2017 #182

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Drug development for NASH

Active drug Placebo

Baseline liver biopsy 2nd liver biopsy in 1-2 years

Conditional approval if:

  • NASH resolution without worsening of fibrosis

OR

  • Fibrosis improvement without worsening of NASH

Follow-up for long-term clinical outcomes

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Challenges in drug development

  • Heavy reliance on liver biopsy
  • Competition for suitable subjects
  • Studies underpowered for clinical outcomes
  • The introduction of the first NASH treatment(s) will affect

retention and management of subjects in ongoing or subsequent trials

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Mechanisms and effects

  • f NASH drugs

Drug Mechanism Resolution

  • f NASH

Fibrosis regression Vitamin E Anti-oxidant ✓ X Pioglitazone PPAR-gamma agonist ✓ X Liraglutide GLP-1 agonist ✓ X Elafibranor PPAR-alpha/delta agonist ✓ X Obeticholic acid FXR agonist ? ✓ Selonsertib ASK-1 inhibitor ? ✓ Cenicriviroc CCR2/5 antagonist X ✓ METABOLIC ANTI-INFLAMMATORY

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Combination of ASK1 and acetyl-coA carboxylase inhibitors in animal models

Bates et al. AASLD 2017 #425

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Thank you very much!

State Key Laboratory of Digestive Disease

  • Prof Henry Chan
  • Prof Grace Wong
  • Angel Chim
  • Carmen Chan
  • Sally Shu
  • Julie Leung
  • Pete Tse
  • Katherine Kwan
  • HY Li

Department of Anatomical and Cellular Pathology

  • Dr Paul Choi
  • Prof Anthony Chan

Vincent Wong wongv@cuhk.edu.hk

Department of Imaging and Interventional Radiology

  • Prof Winnie Chu
  • Dr Jill Abrigo
  • Dr David Yeung

Australian National University

  • Prof Geoff Farrell
  • Prof Shiv Chitturi

University of Sydney

  • Prof Jacob George

University of Malaya

  • Prof K L Goh
  • Prof W K Chan

University of Bordeaux

  • Prof Victor de Lédinghen